Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms

Tong, Ling; Yu, Wei; Chen, Lei; Selyutin, Oleg; Dwyer, Michael P.; Nair, Anilkumar G.; Mazzola, Robert; Kim, Jae‐Hun; Sha, Deyou; Yin, Jingjun; Ruck, Rebecca T.; Davies, Ian W.; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Liu, Rong; Agrawal, Sony; Xia, Ellen; Curry, Stephanie; McMonagle, Patricia; Bystol, Karin; Lahser, Frederick; Carr, Donna; Rokosz, Laura L.; Ingravallo, Paul; Chen, Shiying; Feng, Kung-I; Cartwright, Mark E.; Asante‐Appiah, Ernest; Kozlowski, Joseph A.

doi:10.1021/acs.jmedchem.6b01310

Cited by 43 publications

(29 citation statements)

References 30 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[1,2-c] [1,3] benzoxazine-3,10-diyl]bis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2, 1-ethanediyl]]]bis[carbamic acid] C,C=-dimethyl ester (Fig. 2), an NS5A inhibitor, was prepared as reported previously (38).…”

Section: Discussionmentioning

confidence: 99%

“…We initiated an effort to synthesize a novel pangenotype NS5A inhibitor with a higher barrier to resistance and improved activity against the common RASs (28-37). Our efforts culminated in the discovery of ruzasvir (RZR) (formerly MK-8408), which has shown robust efficacy in patients infected with HCV (38). In this report, we summarize the preclinical antiviral characterization of ruzasvir that led to its clinical development for HCV infection.…”

mentioning

confidence: 99%

See 1 more Smart Citation

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

Asante‐Appiah

Liu

Curry

et al. 2018

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Inhibition of NS5A has emerged as an attractive strategy to intervene in hepatitis C virus (HCV) replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with 50% effective concentrations (ECs) of 1 to 4 pM in Huh7 or Huh7.5 cells bearing replicons for HCV genotype 1 (GT1) to GT7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs), with the exception of M28G. resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31, and 93 across genotypes. Substitutions at position 93 were more common in GT1 to -4, while changes at position 31 emerged frequently in GT5 and -6. With the exception of GT4, the reintroduction of selected RASs conferred a ≥100-fold potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with an NS3/4A protease inhibitor (grazoprevir) and an NS5B polymerase prodrug (uprifosbuvir) was additive to synergistic, with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

Asante‐Appiah

Liu

Curry

et al. 2018

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition to the high prevalence of RASs, the C‐SURGE population was enriched for cirrhosis (43%) and GT1a infection (86%). The enhanced activity of ruzasvir against common NS5A RASs in GT1 infection, including Y93H, combined with the high barrier to resistance of a three‐drug regimen (including a nucleotide inhibitor), likely contributed to the high efficacy …”

Section: Discussionmentioning

confidence: 99%

“…The development of regimens that include new members of a drug class with potency against RASs may further bolster the efficacy of triple‐drug regimens. The combination of grazoprevir, an NS3/4A protease inhibitor, ruzasvir (MK‐8408), a next‐generation pan‐genotypic NS5A inhibitor, and uprifosbuvir (MK‐3682), an NS5B polymerase nucleotide inhibitor, is under evaluation as a fixed‐dose combination for the treatment of HCV infection. In the phase 2 C‐CREST studies, this combination administered for 8, 12, or 16 weeks was highly effective in treatment‐naïve GT1‐, 2‐, or 3‐infected participants with or without cirrhosis (Child‐Pugh class A), even among those with naturally occurring NS3 or NS5A RASs .…”

mentioning

confidence: 99%

Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The most recent study suggested that NS5A was a key factor in HCV treatment (Ikeda et al, 2016). Moreover, many NS5A inhibitors have been proven to effectively treat HCV (Gane et al, 2016), such as BMS-790052 (Gao et al, 2010), MK-8742 (Coburn et al, 2013; Yu et al, 2016), MK-8408 (Ling et al, 2016), ABT530 (Lin et al, 2015), GS-5816 (Mogalian et al, 2015), etc. Because drugs are expensive and have a resistance barrier, it is essential to identify the NS5A inhibition mechanism that can offer a new strategy for the future treatment of HCV.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C Virus Nonstructural 5A Protein (HCV-NS5A) Inhibits Hepatocyte Apoptosis through the NF-κb/miR-503/bcl-2 Pathway

Xie

Xing

Wang

2017

Molecules and Cells

View full text Add to dashboard Cite

The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus (HCV) RNA genome is a multifunctional phosphoprotein. To analyse the influence of NS5A on apoptosis, we established an Hep-NS5A cell line (HepG2 cells that stably express NS5A) and induced apoptosis using tumour necrosis factor (TNF)-α. We utilised the MTT assay to detect cell viability, real-time quantitative polymerase chain reaction and Western blot to analyse gene and protein expression, and a luciferase reporter gene experiment to investigate the targeted regulatory relationship. Chromatin immunoprecipitation was used to identify the combination of NF-κB and miR-503. We found that overexpression of NS5A inhibited TNF-αinduced hepatocellular apoptosis via regulating miR-503 expression. The cell viability of the TNF-α induced Hep-mock cells was significantly less than the viability of the TNF-α induced Hep-NS5A cells, which demonstrates that NS5A inhibited TNF-α-induced HepG2 cell apoptosis. Under TNF-α treatment, miR-503 expression was decreased and cell viability and B-cell lymphoma 2 (bcl-2) expression were increased in the Hep-NS5A cells. Moreover, the luciferase reporter gene experiment verified that bcl-2 was a direct target of miR-503, NS5A inhibited TNF-α-induced NF-κB activation and NF-κB regulated miR-503 transcription by combining with the miR-503 promoter. After the Hep-NS5A cells were transfected with miR-503 mimics, the data indicated that the mimics could reverse TNF-α-induced cell apoptosis and blc-2 expression. Collectively, our findings suggest a possible molecular mechanism that may contribute to HCV treatment in which NS5A inhibits NF-κB activation to decrease miR-503 expression and increase bcl-2 expression, which leads to a decrease in hepatocellular apoptosis.

show abstract

Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms

Cited by 43 publications

References 30 publications

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure

Hepatitis C Virus Nonstructural 5A Protein (HCV-NS5A) Inhibits Hepatocyte Apoptosis through the NF-κb/miR-503/bcl-2 Pathway

Contact Info

Product

Resources

About